1. Field of the Invention
The present invention relates to new anticonvulsants drugs and pharmaceutical compositions containing the anticonvulsants drugs and methods of treating with the drugs.
2. Description of Related Art
GABA is an inhibitory neurotransmitter which plays an important role in the control of neuronal activity in the mammalian central nervous system-CNS [Porter, 1986]. A deficiency in brain GABA levels, has been shown to cause convulsions or epilepsy [Dreifuss, 1987; "GABA (1976)]. Therefore, drugs which increase the amount of GABA available in the brain for neurotransmission have the potential of becoming anticonvulsants and antiepileptic agents. GABA derivatives, such as gamma-vinyl-GABA (GVG) [Mumford and Canon, 1994] and gabapentin [Chadwick (ed), 1993] are two new antiepileptics which have been approved in recent years. Next to GABA, glycine is one of the most important inhibitory neurotransmitter amino acids. Glycine itself does not readily cross the blood-brain barrier due to its zwitterionic character and the absence of an active transport. Similar to GABA, glycine has also been incorporated into the new antiepileptic agent--milacemide [Roba et al, 1986] and remacemide [Clark et al, 1995]. Several reports have shown that co-administration of glycine and other antiepileptics, such as carbamazepine, phenobarbital and GVG, potentiate the anticonvulsant activity in several rats models, due to synergism [Liu et al, 1990; Toth and Lajtha, 1984; Wood et al, 1988; Seiler and Sarhan, 1984; Peterson et al, 1990]. However, neither GABA nor glycine are effective upon oral or systemic administration due to their inability to cross the blood brain barrier (BBB) and their liver metabolic deactivation, which minimizes their availability to the brain [Krogsgaard-Larsen et al, 1988].
Lambert et al. [1994] reported that a glycine derivative N-benzyloxy-carbonylglycine (Z-glycine) was found to be far more active than glycine in rats following chemically and electrically induced seizures. Subsequently, the anticonvulsant activity of ester and amide-type lipid conjugates of glycine and N-benzyloxycarbonylglycine (Z-glycine) were evaluated utilizing the maximal electroshock (MES) and the strychnine tests [Lambert et al, 1996]. In all cases the Z-glycine derivatives were always more potent than the corresponding glycine derivatives with the amide lipid being more active than the ester derivatives [Lambert et al, 1996].
Applicants recently explored the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of N-phthaloyl and N-valproyl derivatives of GABA and glycine [Salach et al, 1994; Hadad and Bialer, 1995; U.S. Pat. No. 5,585,358]. Out of the valproyl derivatives only valproyl glycinamide showed a good anticonvulsant activity in both mice and rats due to its better pharmacokinetic profile [Hadad and Bialer, 1995]. N-valproyl glycinamide (TV 1901) is currently undergoing phase I clinical trials [Bialer et al, 1996A]. Subsequently, applicants developed and evaluated analogues and isomers of TV 1901 which showed good anticonvulsant activity in rodents such as tetramethylcyclopropylcarbonyl glycinamide [Bialer et al, 1996B], N-2-enevalproyl glycinamide, valnoctyl glycinamide and diisopropyl acety glycinamide [Hadad and Bialer, 1997]. These four derivatives of TV 1901 showed, in mice and rats, similar anticonvulsant activity and safety margins to that of the parent compound.
However, it would be useful to have additional anticonvulsant compounds since patients can become refractory to one drug over time or have unwanted side effects or reactions (neurotoxicity) when the drugs are being used to control seizures in the patient. Further, about 30% of epileptic patients are not seizure free with the existing antiepileptic drugs. The larger the number of drugs available, the more ability to design an effective individual therapeutic protocol for each patient. Therefore, the current study was designed in order to investigate the anticonvulsant activity, neurotoxicity, and safety margin of a series of amide derivatives of glycinamide (Table 1, compounds I-XI and referred to hereinafter by the roman numeral assigned therein) and to assess the pharmacokinetics of the active compounds. This pharmacokinetic pharmacodynamic relations study led to the discovery of glycinamide derivatives which are, unexpectedly, new anticonvulsant agents as shown herein.